The long-term goal of our research program is to elucidate the in vivo pathological significance of a novel molecular mechanism, which may be important for the regulation of genes in response to over activity of the angiotensin type 1 receptor (AT1R). Angiotensin II (AngII) is the classical mediator of the effects of the renin- angiotensin system on the cardiovascular homeostasis. This receptor regulates gene expression targeted by the AT1R blockers (ARB), a widely used class of anti-hypertensive drugs that are currently in trial for heart failure (HF) prevention. Inhibition of AT1R in vascular, renal, neuronal and cardiac cells by ARBs protects, but unregulated AT1R activation causes disease states such as hypertension, renal failure, cardiac hypertrophy and progression to HF. We have discovered a novel AT1R signaling paradigm, wherein, Gaa2?12 mobilizes into the nucleus. In the nucleus, G2 functions as an epigenetic modulator of gene expression programs. Thus, G2?12 appears to function as a novel AT1R-to-nucleus messenger that mediates AngII-induced regulation of genes. The goal of this project is to understand the in vivo significance of hither-to-unknown consequences of G2 functions in the nucleus which may be useful for targeted therapy. Currently, it is unknown whether G2 translocation is prevalent in human disease states. No experimental models for studying enhanced G2 functions in the nucleus exist and there are no pharmacological tools to modulate G2 interactions with nuclear targets. To overcome these barriers would require high-risk innovation. The overall objectives of this application are to validate the relevance of the phenomenon in a human disease state; develop new experimental models to study the role of G2 in the nucleus and to develop small molecules to modulate nuclear functions of G2. Our central hypothesis is that exaggerated nuclear translocation of G2 contributes to sustained or chronic transcriptional activation leading to pathophysiological responses. We will pursue the following specific aims; (i) Determine interactions of G2 in the nuclear proteome of in vivo disease models including human heart failure samples; (ii) Evaluate pathological consequences of enhanced G2 function in the nucleus in a novel transgenic mouse model; (iii) Develop small molecule probes for disrupting G2 interaction with transcription factors. If the AT1R activity is not regulated properly, AngII stimulus becomes chronic and can damage the tissue, as well as contribute to chronic disorders of myocardium. A clear understanding of novel transcription regulatory mechanisms is important to improve the therapeutic application of ARBs. These proposed studies will advance our knowledge of AT1R biology.